在过去的100年中,在延长人类预期寿命和抗击主要传染病方面取得了巨大进展。今天,医学科学面临的主要挑战是与年龄有关的疾病,包括癌症,心脏病,肺部疾病,肾脏疾病,和迟发性神经退行性疾病。其中,只有神经退行性疾病代表的一类疾病知之甚少,没有一般的预防或治疗策略存在。这些疾病,其中包括阿尔茨海默病,帕金森病,亨廷顿病,传染性海绵状脑病,和肌萎缩侧索硬化症(ALS),通常是致命的,无法治愈。本综述的第一部分总结了迟发性神经退行性疾病的多样性和共同特征,特别关注蛋白质错误折叠和聚集-这是分子病理学中反复出现的主题。第二部分集中在ALS的特殊情况下,一种以中枢神经系统运动神经元死亡为特征的迟发性神经退行性疾病,导致瘫痪和病人死亡.在10%的显示家族遗传的ALS病例中(家族性ALS),最大的子集是由SOD1基因突变引起的,编码Cu,Zn超氧化物歧化酶(SOD1)。SOD1异常的动力学稳定性为SOD1相关ALS可能涉及的构象状态的详细结构表征提供了独特的机会。这篇综述讨论了过去探索稳定性的研究,折叠,和SOD1的错误折叠行为,以及使用错误折叠途径的详细知识来靶向ALS和其他神经退行性疾病的分子机制的治疗可能性。
Enormous strides have been made in the last 100 years to extend human life expectancy and to combat the major infectious diseases. Today, the major challenges for medical science are age-related diseases, including cancer, heart disease, lung disease, renal disease, and late-onset neurodegenerative disease. Of these, only the neurodegenerative diseases represent a class of disease so poorly understood that no general strategies for prevention or treatment exist. These diseases, which include Alzheimer\'s disease, Parkinson\'s disease, Huntington\'s disease, the transmissible spongiform encephalopathies, and amyotrophic lateral sclerosis (ALS), are generally fatal and incurable. The first section of this review summarizes the diversity and common features of the late-onset neurodegenerative diseases, with a particular focus on protein misfolding and aggregation-a recurring theme in the molecular pathology. The second section focuses on the particular
case of ALS, a late-onset neurodegenerative disease characterized by the death of central nervous system motor neurons, leading to paralysis and patient death. Of the 10% of ALS cases that show familial inheritance (familial ALS), the largest subset is caused by mutations in the SOD1 gene, encoding the Cu, Zn superoxide dismutase (SOD1). The unusual kinetic stability of SOD1 has provided a unique opportunity for detailed structural characterization of conformational states potentially involved in SOD1-associated ALS. This review discusses past studies exploring the stability, folding, and misfolding behavior of SOD1, as well as the therapeutic possibilities of using detailed knowledge of misfolding pathways to target the molecular mechanisms underlying ALS and other neurodegenerative diseases.